We report on what we believe to be the first published case of a subacute course of herpes simplex virus type 1 encephalitis in a patient with asymptomatic chronic lymphocytic leukemia w
Trang 1C A S E R E P O R T Open Access
Subacute herpes simplex virus type 1 encephalitis
as an initial presentation of chronic lymphocytic leukemia and multiple sclerosis: a case report
Rashi L Singhal*, Lourdes C Corman
Abstract
Introduction: Herpes simplex virus type 1 encephalitis presents acutely in patients who are immunocompetent
We report on what we believe to be the first published case of a subacute course of herpes simplex virus type 1 encephalitis in a patient with asymptomatic chronic lymphocytic leukemia who subsequently developed multiple sclerosis
Case presentation: A 49-year-old Caucasian woman with a history of fever blisters presented to our emergency department with a history of left temporal headache for four weeks, and numbness of the left face and leg for two weeks A complete blood count revealed white blood cells at 11,820 cells/mL, with absolute lymphocytes at 7304 cells/mL The cerebrospinal fluid contained 6 white blood cells/μL, 63 red blood cells/μL, 54 mg glucose/dL, and
49 mg total protein/dL Magnetic resonance imaging of the brain revealed meningoencephalitis and bilateral ventriculitis Cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 was positive, and our patient’s symptoms resolved after ten days of treatment with parenteral aciclovir Incidental findings on peripheral blood smear and flow cytometry testing confirmed chronic lymphocytic leukemia Then, one month later, she developed bilateral numbness of the hands and feet; a repeat cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 at this time was negative A repeat magnetic resonance imaging scan showed an expansion of the peri-ventricular lesions, and the cerebrospinal fluid contained elevated oligoclonal bands and myelin basic protein A brain biopsy revealed gliosis consistent with multiple sclerosis, and our patient responded
to treatment with high-dose parenteral steroids
Conclusion: Herpes simplex virus type 1 encephalitis is a rare presentation of chronic lymphocytic leukemia Our patient had an atypical, subacute course, presumably due to immunosuppression from chronic lymphocytic
leukemia This unusual case of herpes simplex virus type 1 encephalitis emphasizes the importance of T cell
function in diseases of immune dysregulation and autoimmunity such as chronic lymphocytic leukemia and
multiple sclerosis It raises the question of whether atypical presentations of herpes simplex virus encephalitis warrant deliberations on immunocompetence The development of multiple sclerosis in our patient so soon after she received treatment for herpes simplex virus type 1 encephalitis raises the possibility that herpes simplex virus type 1 encephalitis in patients who are immunosuppressed may trigger multiple sclerosis
Introduction
Herpes simplex virus type 1 (HSV-1) encephalitis is the
most common cause of adult encephalitis worldwide It
classically occurs in patients under the age of 20 years
due to primary infection, or in patients over the age of
50 years due to reactivation of latent infection It is
thought to occur sporadically in patients who are immu-nocompetent at the same rate as it does in patients who are immunocompromised [1]
HSV-1 encephalitis usually presents acutely, with gen-eral and focal signs of cerebral dysfunction such as fever, headache, altered mental status, behavioral changes, con-fusion, seizures, focal neurological findings, and abnor-mal cerebrospinal fluid (CSF) findings The CSF of patients with HSV-1 encephalitis typically demonstrates
* Correspondence: rashi.l.singhal@gmail.com
The University of Alabama at Birmingham, Huntsville, Alabama, USA
© 2011 Singhal and Corman; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
Trang 2a lymphocytic pleocytosis (white blood cells (WBC): 10 to
500 cells/μL), and erythrocytosis (red blood cells (RBC):
10 to 500 cells/μL) Levels of protein may be elevated to
60 to 700 mg/dL, and levels of glucose may be normal or
slightly decreased (30 to 40 mg/dL)
Imaging of the brain with magnetic resonance imaging
(MRI) classically demonstrates high signal intensity of
the temporal lobe Electroencephalography (EEG) results
may show focal temporal abnormalities, such as spikes
and slow waves or periodic sharp wave patterns A
diag-nosis of HSV encephalitis is confirmed with
identifica-tion of HSV in the CSF via polymerase chain reacidentifica-tion
(PCR) testing or, less commonly, with identification of
HSV in brain tissue via biopsy
It is well established that patients with defects in
cell-mediated immunity are at increased risk of severe oral
or genital HSV infection; however, an increased
fre-quency of HSV meningoencephalitis has not been
reported We report a subacute course of HSV-1
menin-goencephalitis in a patient with undiagnosed chronic
lymphocytic leukemia (CLL), who presented with
biopsy-proven multiple sclerosis (MS) shortly after
receiving treatment for HSV-1 encephalitis
Case presentation
A 49-year-old Caucasian woman with a history of
migraines and herpes labialis presented to our
emer-gency department (ED) with headache, and numbness
and tingling in the left side of the face and her left leg
She related a history of recurrent sinusitis related to
sea-sonal allergies, but with no recent nasal or pulmonary
symptoms She had developed peri-oral fever blisters, a
low-grade fever, and a disabling left temporal headache
four weeks earlier Her headache was unlike the typical
migraines that she periodically experienced, which
usually responded to a combination of acetaminophen,
aspirin, and caffeine In addition, she experienced
nau-sea, vomiting, and decreased appetite in association with
her headaches that were accompanied by a 7.7 kg weight
loss She also exhibited personality changes and
short-term memory loss Her blisters healed in two weeks, but
her headache and fatigue persisted She subsequently
developed numbness and subjective weakness in the left
side of her face and her left leg one week prior to
pre-sentation She sought care from her primary care
provi-der, who diagnosed her with Bell’s palsy and prescribed
metoclopramide for her nausea She was also referred to
a neurologist who began treatment with aspirin for
sus-pected transient ischemic attack An MRI of the brain
was pending at the time of her presentation to the ED
On admission, our patient’s temperature was 37.9°C,
blood pressure 166/96 mmHg, pulse rate 89
beats/min-ute, respiration rate 18 breaths/minbeats/min-ute, and oxygen
saturation 97.5% on room air Her mental status and
affect were normal The distribution of dysesthesias was confirmed to be in the V2/V3 and L4/L5 dermatomes
on physical examination No motor deficits, other neu-rological abnormalities, or lymphadenopathy were noted A basic metabolic panel was remarkable for 3.2 mEq potassium/L (normal range 3.5 to 5.0) A com-plete blood count revealed 11.82 × 109cells/L for WBC, with 7.304 × 103cells/μL for absolute lymphocytes Her CSF was clear and contained WBC: 6 cells/μL (89% lym-phocytes), RBC: 63 cells/μL, 54 mg glucose/dL, and
49 mg total protein/dL; cell counts were taken from the fourth tube of CSF collected Results of a chest radio-graph were normal, and an MRI scan of the brain showed left greater than right ventriculitis, basal menin-gitis, and encephalitis of the peri-ventricular and right basal ganglia white matter (see Figure 1)
Treatment with intravenous dexamethasone, ceftriax-one, and aciclovir was initiated and the low potassium was replaced Our patient’s headache and dysesthesias rapidly improved On day 2, the hospital’s pathology lab reported small, mature-appearing lymphocytes and smudge cells in her peripheral blood smear Further immunological investigation revealed 259 absolute CD4+ T cells (normal range 400 to 1500), 389 absolute CD8+ T cells (normal range 275 to 780), and a CD4/ CD8 ratio of 0.7 (normal range 0.9 to 3.7) Results of a CSF polymerase chain reaction (PCR) test for HSV-1 were positive, and results of serum HIV-1 and 2 anti-body tests were negative Ceftriaxone and dexametha-sone were subsequently discontinued The serum and CSF studies performed to rule out other infectious and vasculitic processes are listed in Table 1
A diagnosis of CLL was confirmed by the expression
of CD5, CD19, and CD20 antigens on monoclonal B cells with light chain restriction on blood flow cyto-metry Fluorescent in situ hybridization later revealed a
13 q deletion, the most common cytogenetic abnormal-ity seen among patients with CLL Our patient’s g-globulin level was 839 mg/dL (normal range 700 to 1600) After eight days on intravenous aciclovir, her symp-toms had completely resolved and she was discharged on oral valaciclovir She remained well for the next few weeks Then, one month after discharge, she developed new bilateral numbness of the hands and feet and was found
to have cervical lymphadenopathy on physical examina-tion A repeat MRI showed increased numbers and size
of peri-ventricular lesions (see Figure 1), and she was readmitted A repeat CSF PCR test for HSV-1 was nega-tive, but 10 oligoclonal bands and a myelin basic protein level of 5.7 ng/mL (normal value <1.5) were found Table 2 gives details of the other laboratory test results for comparison between our patient’s first and second admissions Computed tomography (CT) scans revealed extensive cervical lymphadenopathy, slightly enlarged
Trang 3axillary nodes bilaterally, and early lymphadenopathy
among the mesentery A brain biopsy was performed to
rule out CNS lymphoma, and it demonstrated gliosis
consistent with MS with no evidence of lymphoma (see
Figure 2) She received high-dose parenteral steroids for
five days, with symptom resolution occurring within the
first two to three days She was discharged on oral
predni-sone treatment and followed up by her neurologist and
oncologist At six months later our patient was still
asymp-tomatic, having started interferon-b therapy for MS and
not yet needing treatment for Rai stage zero CLL
Discussion
HSV-1 encephalitis usually presents fulminantly in
immu-nocompetent individuals with fever, altered mental status,
seizures, CSF and EEG findings, and temporal lobe lesions
on MRI Our patient’s illness began with recurrent herpes
simplex labialis, which spread to the left trigeminal nerve
and left L5 nerve root over the course of four weeks
Besides her dysesthesias, her symptoms included
head-ache, low-grade fever, weight loss, mild personality change
and short-term memory loss, which were no longer
exhib-ited on presentation Her CSF contained mildly elevated
levels of lymphocytes (WBC: 6 cells/μL), erythrocytes
(RBC: 63 cells/μL), and protein (49 mg/dL); owing to the
fact that cell counts were taken from the fourth tube
col-lected, the probability of a traumatic lumbar puncture is
low Beyond her MRI findings of peri-ventriculitis and
basal meningitis, particularly over the brainstem, our patient had no temporal lobe abnormalities, although approximately 10% of patients with PCR-proven HSV encephalitis do not demonstrate temporal lobe involve-ment In addition, other cases of brainstem encephalitis due to HSV have been reported with viral reactivation possibly occurring in the trigeminal nerve (relevant refer-ences are available upon request from the corresponding author) Regarding involvement of white matter, other cases of extratemporal HSV encephalitis have also shown this pattern on neuroimaging, particularly during chronic
or subacute phases of illness, often being associated with clinical relapse and viral persistence and sometimes show-ing demyelination in addition to edema, inflammatory change, and viral inclusions on a microscopic level (rele-vant references are available upon request from the author) Overall, our patient’s clinical presentation, bor-derline pleocytosis in the CSF, and extratemporal findings
on MRI were consistent with a more subacute course of HSV-1 encephalitis proven by PCR, presumably due to immunosuppression from CLL
Patients with CLL often manifest hypo-g-globuline-mia and neutropenia early in the course of the disease, with eventual T cell deficiency leading to recurrent sinopulmonary infections with Gram-negative bacteria, fungi, and herpes zoster and simplex viruses However, HSV-1 encephalitis is a rare presentation of CLL Other central nervous system (CNS) infections have
Figure 1 Comparison of brain MRIs between patient ’s first (A) and second (B) admission A) Axial T2-flair MRI from 2 February 2009 demonstrating foci of peri-ventricular hyperintensity (more evident on the left than the right) Other findings included left greater than right lateral ventriculitis, basal meningitis, encephalitis involving the peri-ventricular and right basal ganglia white matter, and enhancing lesions in the left pons and the lower third of the medulla B) Axial T2-flair MRI from 9 March 2009 demonstrating enlargement of prior hyperintense foci and new hyperintensity in the right posterior peri-ventricular white matter Other findings included new enhancing lesions in the splenium of the corpus callosum, decreased enhancement in the right corona radiata and left frontal horn, and unchanged enhancements in the pons and medulla.
Trang 4been reported in patients with CLL, namely progressive
multifocal leukoencephalopathy, West Nile virus
ence-phalitis, and Listeria monocytogenes encephalitis The
occurrence of HSV-1 encephalitis in patients who are
immunocompromised has rarely been reported Classic
clinical presentations with atypical laboratory studies
have been described in a patient with metastatic colon
cancer four weeks after receiving chemotherapy [2],
three patients who were immunosuppressed with
either Hodgkin’s or non-Hodgkin’s lymphoma [3-5],
and another patient with glioblastoma multiforme on
dexamethasone [5] Atypical clinical presentations of
HSV encephalitis have been described in patients
receiving steroids, and also occur in 2% of patients
with human immunodeficiency virus (HIV) with
neu-rological symptoms, usually in association with CD4 T
cell counts <200 cells/μL [6]
The literature exploring the association of MS with CLL is very limited Neither the development of CLL prior to the development of MS, nor the reverse, have been shown to have an association in retrospective stu-dies ([7]; additional references are available upon request from the author) Only one study has shown an increased risk of Hodgkin’s and non-Hodgkin’s lym-phoma in first-degree relatives of patients with MS, and this is thought to be related to shared environmental and constitutional factors such as infection with Epstein-Barr virus or expression of the HLA-DR2 allele The development of clinical symptoms and signs of
MS in our patient so soon after her episode of HSV-1 encephalitis, as well as her earlier atypical peri-ventricu-lar pattern of MRI findings, suggests a possible associa-tion between the infecassocia-tion and subsequent diagnosis of
MS On the one hand, it is possible that our patient’s
Table 1 Results of infectious and vasculitic and neoplastic studies performed on patient’s first admission
range or value)
CSF studies Result (normal range) Ehrlichia Ab titers
Anaplasma phagocytophilum IgG <1:64 (<1:64) Aerobic/anaerobic
culture with Gram stain
No organisms seen, no growth
at 3 days Ehrlichia chaffeensis IgG <1:64 (<1:64)
Bartonella Ab titers
Bartonella henselae IgG and IgM <1:128 and <1:20
(<1:128 and <1:20)
Fungal preparation and culture
No fungal elements seen, no fungus recovered at 4 weeks Bartonella quintana IgG and IgM <1:128 and <1:20
(<1:128 and <1:20)
smear
No AFB seen, no AFB recovered at 8 weeks.
Viral hepatitis panel
LCMV IgG and IgM Ab titer <1:16 and <1:20
(<1:16 and <1:20)
LCMV IgG and IgM Ab titer
<1:1 and <1:1 (<1:1 and <1:1)
Toxoplasma IgG and IgM Ab titer 36 IU/mL and
<0.55 (<4 and
<0.55)
WNV PCR Negative
Expanded ANA screen: Abs to dsDNA, chromatin, Sm, RNP, Sm-RNP,
Ribosomal protein, SS-A, SS-B, Jo-1, Scl-70, and Centromere B
Negative Serum protein electrophoresis No monoclonal
bands identified
Ab = antibody; ACE = angiotensin-converting enzyme; AFB = acid-fast bacilli; Ag = antigen; ANA = anti-nuclear antibody; CMV = cytomegalovirus; CRP = C-reactive protein; dsDNA = double-stranded DNA; ESR = erythrocyte sedimentation rate; HA = hepatitis A; HBcAb = anti-hepatitis B core antibody; HBsAg = hepatitis B surface antigen; LCMV = lymphocytic choriomeningitis virus; PCR = polymerase chain reaction; RNP = ribonucleoprotein; RPR = rapid plasma reagin; SS-A/B = Sjögren ’s syndrome antigen A/B; VDRL = Venereal Disease Research Laboratory; VZV = varicella zoster virus; WNV = West Nile virus.
Trang 5initial illness was an early manifestation of MS with
asymptomatic HSV-1 colonization in the CNS, and that
her initial improvement could be attributable to
receiv-ing dexamethasone for 1 day Of note, detection of HSV
DNA in CSF by PCR has a sensitivity of 98% and a
spe-cificity of >95% [8] True positives have been reported
in patients who are asymptomatic, and false positives
have been reported due to cross-contamination
Addi-tionally, the MRI from our patient’s first admission
demonstrated basal meningitis, which is an atypical
fea-ture of MS (see Figure 3) On the other hand, our
patient’s recent recurrence of herpes labialis, the positive
CSF PCR for HSV-1, and her continued improvement
over nine days while receiving intravenous aciclovir
sup-port the argument that HSV-1 infection was the reason
for her initial illness Regarding the nature of the illness,
CSF PCR for HSV has been recently used by others to
diagnose mild cases of HSV encephalitis, to diagnose atypical cases of adult HSV encephalitis involving poly-radiculoneuritis and inflammatory syndrome with ara-chnoiditis, and to define a pathogenic role of HSV in episodes unlikely to be entirely CNS viral infections (relevant references are available upon request from the author) Furthermore, the fact that our patient’s repeat CSF PCR result for HSV-1 was negative on her second admission helps support that her initial encephalitis was related to HSV-1 even if some demyelination due to MS had already begun Although studies of the CSF such as oligoclonal banding were not performed or indicated during her first admission to explore the likelihood of
MS, the patient denied any history of urinary inconti-nence, vision loss, unilateral blurred vision, double vision, gait disturbance, or paresthesias before her cur-rent illness However, the expansion of previous areas of
Table 2 Comparison of laboratory studies performed during patient's first and second admissions
Laboratory studies First admission (2 to 9 February) Second admission (11 to 21 March) Normal range or value Complete blood count
CSF lumbar puncture
CSF rapid PCR for HSV-1 Positive Negative
Oligoclonal banding
CSF IgG index
This table demonstrates the available studies performed during each of the patient's admissions that pertain to her diagnoses of chronic lymphocytic leukemia (complete blood count, CSF cytology, CSF flow cytometry), Herpes simplex virus type-1 encephalitis (CSF lumbar puncture, CSF rapid PCR for HSV-1), and multiple sclerosis (oligoclonal banding, CSF IgG index, CSF myelin basic protein).
CSF = cerebrospinal fluid; HSV = herpes simplex virus; PCR = polymerase chain reaction; RBC = red blood cells; WBC = white blood cells.
Trang 6peri-ventriculitis on the patient’s second admission do
raise the possibility of her first admission involving
con-current HSV-1 encephalitis and MS
A recent study of patients with MS has demonstrated
alterations in dendritic cell antigens and interferon
expression in response to HSV-1 challenge to
mononuc-lear cells [9] Whether such an impaired immune
response to viral infection is present before the
develop-ment of MS is unknown Additionally, patients with MS
are known to have elevated antibody titers to HSV-1 in
the CSF, but this is purported to be non-specific and
studies of CSF PCR for HSV-1 in patients with MS have
failed to find a statistically significant association [10]
There is evidence of association between infection with
Epstein-Barr virus (EBV) and subsequent diagnosis of
MS, as well as between CNS infection with human
herpesvirus 6 variant A (HHV6A) and concurrent MS [10]; however causal relationships are yet unproven Our patient did not undergo serological EBV testing or CSF studies for HHV6 during her admissions
Conclusion
No definitive association can be inferred regarding the development of MS in our patient so soon after her diag-noses of CLL and HSV-1 encephalitis, but this occur-rence warrants reporting This atypical presentation of HSV-1 infection in a patient with undiagnosed CLL emphasizes the importance of T cell function in diseases
of immune dysregulation and autoimmunity such as CLL and MS It raises the issue of whether patients with atypi-cal presentations of HSV encephalitis deserve a delibera-tion on their state of immunocompetence
Figure 2 Left occipital brain biopsy performed on 15 March 2009 A) Hematoxylin and eosin (H&E) stain (100×) showing a sharp border between relatively normal neuropil inferiorly and a paler area of gliosis representing a lack of myelin superiorly B) H&E stain (200×) showing a peri-vascular cuff consisting of lymphocytes and histiocytes C) H&E stain (400×) showing an inflammatory infiltrate rich with histiocytes D) Immunoperoxidase stain (200×) for CD68 macrophages showing strong positivity in areas of gliosis The final pathological diagnosis was gliosis and reactive changes consistent with demyelinating disease The findings were negative for lymphoma An immunostain for herpes simplex virus (HSV) was also negative Other immunohistochemistry stains were as follows: B cell marker CD20 was positive in a few B cells, T cell marker CD3 was positive for several T cells, B cell marker CD79 was positive in a few B cells, and proliferation marker Ki-67 was low at 3%.
Trang 7Written informed consent was obtained from the patient
for publication of this case report and any
accompany-ing images A copy of the written consent is available
for review by the Editor-in-Chief of this journal
Acknowledgements
We would like to acknowledge pathologist Frank Honkanen MD for
discussing the pathological findings of the brain biopsy with the authors
and procuring the images in Figure 2, trainee physician Pavan Panchavati
MD for reviewing the initial abstract of this case and who admitted the
patient to the emergency department, and hematologist/oncologist Ali
Hachem MD and neurologist Theodros Mengesha MD for reviewing the
abstract and discussing the case with the authors.
Authors ’ contributions
RLS and LCC followed the course of our patient ’s illness in the hospital RLS
collected, analyzed, and interpreted pertinent information from the literature
and patient data including laboratory and imaging studies, biopsy results,
and overall clinical progress LCC reviewed the text and figures with RLS
over several months, making suggestions for revisions and further literature
review All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 24 October 2009 Accepted: 11 February 2011
Published: 11 February 2011
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doi:10.1186/1752-1947-5-59 Cite this article as: Singhal and Corman: Subacute herpes simplex virus type 1 encephalitis as an initial presentation of chronic lymphocytic leukemia and multiple sclerosis: a case report Journal of Medical Case Reports 2011 5:59.
Figure 3 Brain MRI demonstrating basal meningitis during our patient ’s first admission Axial T1-SE fat-suppression contrast-enhanced MRI scans showed abnormal signal intensity of the basal meninges, particularly involving the left cerebellar peduncle (A) and the right anterior mesencephalic-pontine junction (B).